Balloon angioplasty of atherosclerotic arteries results in activation of the coagulation cascade. Several coagulation factors, including Factor Xa and thrombin are mitogenic for vascular smooth muscle cells in vitro and thus may play a role in the restenosis after balloon angioplasty. Specific inhibition of Factor Xa can be achieved with recombinant antistasin (rATS) or tick anticoagulant peptide (rTAP). We hypothesized that inhibition of Xa would limit restenosis after balloon angioplasty in an atherosclerotic rabbit model. Focal femoral atherosclerosis was induced by air desiccation injury and a high cholesterol died in 38 New Zealand White rabbits. Recombinant antistasin (n=20 arteries) or rTAP (n=14 arteries) were administered by intravenous bolus at the time of balloon angioplasty and followed by a 2 hour infusion: controls (n=21 arteries) received bolus heparin alone (150U/kg). Therapeutic prolongation of the activated partial thromboplastin time occurred and therapeutic drug levels were achieved in all animals. Luminal diameter (LD) in mm by quantitative angiography did not differ between treatment groups before or after BA. At 28 days rATS-treated arteries had larger LD than controls, and tended to be less in the rTAP group. Quantitative histopathologic analysis revealed less percent cross-sectional area narrowing by plaque in both rATS or rTAP-treated arteries compared with controls. We conclude that a 2-hour infusion of the potent and specific Xa inhibitors rATS or rTAP at the time of balloon angioplasty reduced angiographic restenosis and resulted in less luminal cross-sectional narrowing by plaque compared to controls.